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Life-Threatening Interaction of Mibefradil and  -Blockers With Dihydropyridine Calcium Channel Blockers
Michael E. Mullins, MD;
B. Zane Horowitz, MD;
Dennis H. J. Linden, MD;
Gregory W. Smith, RPh;
Robert L. Norton, MD;
Jack Stump, MD
JAMA. 1998;280:157-158.
ABSTRACT
Mibefradil is a T-type and L-type calcium channel blocker (CCB) released in the United States in 1997 for management of hypertension and chronic stable angina. Postmarketing surveillance revealed a potential serious interaction between mibefradil and  -blockers, digoxin, verapamil, and diltiazem, especially in elderly patients. The manufacturer voluntarily withdrew mibefradil on June 8, 1998. We describe 4 cases of cardiogenic shock in patients taking mibefradil and -blockers who began taking dihydropyridine CCBs. One case resulted in death; the other 3 survived episodes of cardiogenic shock with intensive support of heart rate and blood pressure. Physicians who are preparing to switch patients' medications from mibefradil to other antihypertensive agents should be aware of these potentially life-threatening drug-drug interactions.
INTRODUCTION
MIBEFRADIL (Posicor, Roche Laboratories Inc, Nutley, NJ) is a long-acting nondihydropyridine calcium channel blocker (CCB) that uniquely blocks both the T (transient) calcium channels and the L (long) calcium channels.1 All other CCBs currently approved for use in the United States block the L channel. Less than a year after its release in mid-1997, almost 200000 Americans were taking mibefradil.2 Roche Laboratories voluntarily withdrew Posicor from the market on June 8, 1998,3 as numerous cytochrome P-450–mediated drug interactions became apparent. We report 4 cases that suggest that switching to dihydropyridine CCBs the day after taking mibefradil may be hazardous.
Report of Cases
Case 1
A 79-year-old woman with hypertension was taking daily doses of mibefradil, 100 mg, propranolol, 160 mg, indapamide, and estrogen. Her blood pressure was poorly controlled and her physician discontinued her mibefradil therapy; he prescribed controlled-release nifedipine, 60 mg daily, to start on the following day. One hour after her first dose of nifedipine, she collapsed at home. She presented to the emergency department (ED) with a systolic blood pressure of 60 mm Hg and junctional bradycardia at 40/min to 50/min. She remained bradycardic with transient improvement in systolic blood pressure to 90 to 100 mm Hg with dopamine infusion at 20 µg/kg per minute, norepinephrine infusion at 28 µg/min, 10 mL of 10% calcium chloride, and 3 L of intravenous fluids. She received additional atropine and calcium without change in her vital signs or electrocardiogram. Serial creatine kinase concentrations were normal.
Her treatment in the intensive care unit included dopamine infusion titrated to a maximal rate of 20 µg/kg per minute and norepinephrine infusion titrated to a maximal rate of 32 µg/min with little improvement in her blood pressure and heart rate. Approximately 10 hours later, when the patient became unresponsive with a systolic blood pressure of 60 mm Hg and a junctional bradycardia at 40/min to 50/min, she received 1 mg of intravenous glucagon. Minutes later, her rhythm deteriorated to asystole. Resuscitation attempt was unsuccessful. Autopsy revealed a normal heart with no evidence of acute myocardial infarction, aortic dissection, or pulmonary embolism.
Case 2
A 55-year-old woman with hypertension, non–insulin-dependent diabetes, and osteoarthritis was taking daily doses of nadolol, 80 mg, and mibefradil, 100 mg, in addition to glimepiride, omeprazole, and oxaprozin. Her blood pressure was considered poorly controlled by her physician, with a heart rate of 72/min, so felodipine, 5 mg, and enalapril, 5 mg, were prescribed. She took the first dose at bedtime with her mibefradil. Five hours later, her husband awoke and found her in distress with altered mental status and substernal chest pain. Her systolic blood pressure at home was approximately 60 mm Hg and she was taken to the ED.
In the ED, she appeared pale with a heart rate of 48/min and a blood pressure of 112/77 mm Hg. Her blood glucose level was 13.6 mmol/L (244 mg/dL). A 12-lead electrocardiogram demonstrated a junctional bradycardia at 34/min. Despite 2 intravenous doses of atropine, 0.5 mg, her heart rate remained 42/min with a blood pressure of 96/55 mm Hg. Shortly thereafter she collapsed in apparent cardiogenic shock. Her heart rate fell into the 30s with a palpable systolic blood pressure of 80 mm Hg. She became obtunded and oliguric. During the remainder of her ED course, her maximal heart rate was 69/min after a total of 2 mg of atropine, 10 mL of 10% calcium gluconate, and an infusion of dopamine at 10 µg/kg per minute. Three mg of intravenous glucagon was administered, after which the patient experienced intense nausea and retching. After metaraminol infusion at 70 µg/min, an additional 20 mL of 10% calcium gluconate, and a total of 4 L of intravenous normal saline were administered, her vital signs improved to a blood pressure of 126/60 mm Hg with a heart rate of 90/min. Serial creatine kinase testing was normal. In the intensive care unit, she continued to be treated with dopamine, 10 µg/kg per minute, and metaraminol, 70 µg/min, with gradual improvement in her mental status and urine output. Pressors were tapered over the next 24 hours. She was discharged 4 days later without sequelae.
Case 3
A 60-year-old woman, whose hypertension remained poorly controlled despite various antihypertensive regimens, was taking mibefradil, 100 mg daily, and extended-release metoprolol, 50 mg daily. Her physician changed her regimen to sustained-release nifedipine, 60 mg daily, with doxazosin, 1 mg daily, and captopril, 25 mg 3 times daily. A few hours after her first doses of the latest regimen, she presented to her physician's office with a systolic blood pressure of 70 mm Hg and heart rate of 50/min. After immediate transfer to the ED, her vital signs remained unchanged despite dopamine infusion, 20 µg/kg per minute, 10 mL of 10% calcium gluconate, and intravenous fluids. Approximately 12 hours later, her blood pressure was 70/39 mm Hg with a heart rate of 60/min despite the addition of norepinephrine. Her urine output was 100 mL over 8 hours. After her hypotension and bradycardia gradually resolved over the next 2 days, she was discharged to home without residual effects.
Case 4
A 60-year-old man with hypertension, hypertensive encephalopathy with lacunar infarction 6 weeks earlier, and non–insulin-dependent diabetes had been taking mibefradil, 100 mg daily, for 6 weeks, in addition to metoprolol, hydrochlorothiazide, quinapril, glyburide, metformin, terazosin, folic acid, and vitamin E. He was found to have poor blood pressure control and his physician stopped treatment with mibefradil and prescribed treatment with nisoldipine, 20 mg, to be started the next day. Within 90 minutes after the first dose of nisoldipine, he developed severe burning chest pain, throat pain, nausea, vomiting, and light-headedness, and presented to the ED with a systolic blood pressure of 80 mm Hg and a heart rate of 40/min. The initial electrocardiogram in the ED showed ST-segment elevation in leads I, V5, and V6. Q waves developed in subsequent electrocardiograms in V4, V5, and V6. The initial serum creatine kinase level was 101 U/L with a creatine kinase–MB of 2; subsequent creatine kinase levels were not available. Echocardiography and angiography confirmed the diagnosis of acute myocardial infarction. The patient required an intra-aortic balloon pump and infusions of dopamine, norepinephrine, and glucagon. He survived and eventually was discharged to home.
Comment
Several studies conducted by the manufacturer have described the overall safety of mibefradil,4 its safety in the elderly,5 and its tolerability with -blockers.6 However, in December 1997, Roche Laboratories issued a warning letter to physicians describing the suppression of sinoatrial node activity, which is most likely to occur in elderly patients concurrently taking -blockers and in patients with resting heart rate less than 55/min.7 The warning letter emphasized that the use of mibefradil with a -blocker, digoxin, verapamil, or diltiazem requires great caution, but it did not mention dihydropyridine CCBs.
On June 8, 1998, Roche Laboratories issued a voluntary withdrawal and recall of Posicor.3 Mibefradil inhibits the P-450 enzyme CYP 3A4 and interferes with the metabolism of at least 26 other medicines.3 The recall letter emphasized the potential for adverse effects from CYP 3A4 inhibition but did not mention a potential for drug-drug interactions with dihydropyridine CCBs taken after mibefradil.
These 4 similar cases demonstrate the potential hazard of beginning a dihydropyridine CCB in a patient already taking mibefradil and a -blocker. These patients had other medical conditions and other medications (such as doxazosin), which may have contributed to the hypotension they experienced. However, the timing of hypotension soon after ingesting the CCB within a day of taking mibefradil suggests that this combination should be avoided. The long half-life of mibefradil (17-25 hours)8 may require a prolonged washout period before considering therapy with another CCB. Furthermore, in patients who do not achieve adequate blood pressure control with mibefradil, which blocks both T-type and L-type calcium channels, CCBs that block only L-type calcium channels would be unlikely to improve blood pressure control.
In response to these and similar cases, Roche Laboratories issued a supplemental letter on June 12, 1998, to advise a delay of 7 days after discontinuation of mibefradil before beginning therapy with most other CCBs and -blockers.9 Felopidine and timolol require a 14-day washout after discontinuation of mibefradil. Angiotensin-converting enzyme inhibitors, angiotensin II antagonists, and diuretics do not require special precautions.
Managing combined myocardial depression and hypotension with CCBs and -blockers is difficult. High-dose glucagon (5-10 mg intravenously) increases intracellular cyclic adenosine monophosphate and produces positive inotropic, dromotropic, and chronotropic effects.10-11 With high doses of glucagon, sterile water and saline are safer diluents than the 0.2% phenol solution provided with the product.12 Repeated doses of calcium are often necessary to overcome the effects of calcium channel blockers.13 No single agent is likely to be effective. Vasopressors, inotropes (such as amrinone14), and temporary pacing may be necessary.
AUTHOR INFORMATION
Because of the public health importance of this report, it was released and posted on the JAMA web site on June 18, 1998.
The authors are grateful to Susan Lu, RPh (Division of Epidemiology and Pharmacovigilance), and Harold Stepper (Freedom of Information staff) of the US Food and Drug Administration, for kindly providing information about the fourth case.
Reprints: Michael E. Mullins, MD, mail code CB 550, 3181 SW Sam Jackson Park Rd, Portland, OR 97201-3098 (e-mail: mullinmi{at}ohsu.edu).
From the Oregon Poison Center, Portland, Ore (Drs Mullins, Horowitz, and Norton); the Rogue Valley Medical Center, Medford, Ore (Drs Linden and Stump); and the Louisiana Poison Control Center, Monroe (Dr Smith).
REFERENCES
1. Mibefradil: a new calcium channel blocker. Med Lett. 1997;39:103-105.
2. Neergaard L. Heart drug pulled from market. Associated Press. June 8, 1998.
3. Voluntary market withdrawal, Posicor [Dear Doctor letter]. Nutley, NJ: Roche Laboratories Inc; June 8, 1998.
4. Kobrin I, Charlon V, Lindberg E, Pordy R. Safety of mibefradil, a new once-a-day, selective T-type calcium channel antagonist. Am J Cardiol. 1997;80:40C-46C.
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5. Bursztyn M, Kadr H, Tilvis R, et al. Mibefradil, a novel calcium channel antagonist, in elderly patients with hypertension: favorable hemodynamics and pharmacokinetics. Am Heart J. 1997;134:238-247.
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6. Alpert JS, Kobrin I, DeQuattro V, et al. Additional antianginal and anti-ischemic efficacy of mibefradil in patients pretreated with a beta-blocker for chronic stable angina pectoris. Am J Cardiol. 1997;79:1025-1030.
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7. Dear Doctor letter. Nutley, NJ: Roche Laboratories Inc; December 18, 1997.
8. Posicor [package insert]. Nutley, NJ: Hoffman-La Roche; December 1997.
9. Important information on drug interaction and therapy substitution for Posicor [Dear Doctor letter]. Nutley, NJ: Roche Laboratories Inc; June 12, 1998.
10. Doyon S, Roberts JR. The use of glucagon in a case of calcium channel blocker overdose. Ann Emerg Med. 1993;22:1229-1233.
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11. Walter FG, Frye G, Mullen JT, Ekins BR, Khasigian PA. Amelioration of nifedipine poisoning associated with glucagon therapy. Ann Emerg Med. 1993;22:1234-1237.
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14. Wolf LR, Spadafora MP, Otten EJ. Use of amrinone and glucagon in a case of calcium channel blocker overdose. Ann Emerg Med. 1993;22:1225.
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